N-alkyl-4-chloro-1H-benzo[c][1,2]thiazine-3-carbaldehyde-2,2-dioxides - New functional benzothiazine derivatives

Article abstract of DOI:10.1002/jhet.5570440627

(Chemical Equation Presented) A synthesis of N-alkyl-4-chloro-1H-benzo[c] [1,2]thiazine-3-carbaldehyde-2,2-dioxides is described. Reactivity of new β-chloroaldehydes is investigated, a number of novel benzo[c][1,2]thiazine derivatives are synthesized and characterized using ¹H, ¹³C-NMR, MS and elemental analysis.

Full text of DOI:10.1002/jhet.5570440627

Nov-Dec 2007
1413
N-Alkyl-4-chloro-1H-benzo[c][1,2]thiazine-3-carbaldehyde-2,2-
dioxides - New Functional Benzothiazine Derivatives
Yulian Volovenko, Tatyana Volovnenko and Kirill Popov*
Organic Synthesis Laboratory
Kyiv National University, Kyiv 01033, Ukraine
Fax: +380(44)5732397; E-mail: popovkirill@bk.ru
January 24, 2007
methoxy, dimethylamino
pyrazolo-anellated
-NMe
-OMe,
2
O
Cl
O
-NH-Ph (hydrazone)
Vilsmeyer-Haack
77-79%
O
O
O
O
oximes
hydrazones
nitriles
NH2OH
S
S
N
R
N
R
PhNHNH2
HO(CH2)2OH
cyclic acetal
CH2(CN)2
Knoevenagel, methylene-malononitrile
thio-acetal
p-Cl-C6H4-SH
R= Alkyl (1-4C), benzyl, 2-Cl-benzyl
A synthesis of N-alkyl-4-chloro-1H-benzo[c][1,2]thiazine-3-carbaldehyde-2,2-dioxides is described.
Reactivity of new ꢀ-chloroaldehydes is investigated, a number of novel benzo[c][1,2]thiazine derivatives
are synthesized and characterized using 1H, 13C-NMR, MS and elemental analysis.
J. Heterocyclic Chem., 44, 1413 (2007).
2-methanesulfonylamino-benzoic acid ethyl ester 2 in
high yield. Triethylamine was used as the base.
Subsequent alkylation of 2 with a range of alkyl halides
in DMF afforded ethyl N-alkyl-methylsulfonylamino-
benzoates 3a-f and was followed by their treatment with
sodium hydride in dry DMF to produce N-alkyl-1H-
benzo[c][1,2]thiazin-4-one-2,2-dioxides 4a-f. The ring
closure occurred in good to excellent yields.
The Vilsmeier-Haack reaction performed with ketones
4a-b,d-e led to ꢀ-chloroaldehydes 5 (Scheme II, Table
1). It was discovered, that if the molar ratio of 4 and
the Vilsmeier reagent is 1:4, then pure N-alkyl-4-
chloro-1H-benzo[c][1,2]thiazine-3-carbaldehyde-2,2-
dioxides 5a-b,d-e could be obtained and in good to
excellent yields.
During the last 25 years, chloroformylation became a
convenient transformation providing access to the
intermediates widely used in pharmaceutical-directed
organic synthesis [6-10]. The novel ꢀ-chloroaldehyde
compounds 5 contain two electrophilic centers: the carbon
atom C-4 of the benzothiazine system and the carbon
atom of the aldehyde group. We have investigated the
reactivity of both centers.
INTRODUCTION
Benzo[c][1,2]thiazine nucleus is present in many
synthetic pharmacologically active compounds. The
derivatives of this heterocycle are shown to possess anti-
inflammatory, antiviral, CNS-depressive properties [1].
Much attention has been focused on approaches for the
construction of the 1H-benzo[c][1,2]thiazin-4-one system.
The synthesis of this compound starting from sulfoacetic
acid was reported [2a-b]. Also, new methods of accessing
these important compounds continue to be developed.
Several hetero-annelated benzothiazine analogues were
synthesized [3-4].
Nevertheless, the methylene group, carbonyl moiety
and the fused benzene ring of benzothiazinone provide an
opportunity for further modification. The introduction of
functional groups in the unsubstituted positions of
thiazine, and heterocycles fused at the [c] side of thiazine
ring are the objectives of actual research.
RESULTS AND DISCUSSION
We have carried out the synthesis [5] of several N-
alkyl substituted benzothiazines (Scheme I, Table 2).
Sulfonylation of 2-aminobenzoic acid ethyl ester 1
with methanesulfonylchloride in dry dioxane provided
Scheme 3 illustrates reactions of ꢀ-chloroaldehydes 5a-
d with hydroxylamine, phenyl-hydrazine, ethane-1,2-diol,
Scheme I
O
O
O
O
MeSO2Cl, Et3N
1,4-dioxane, 0°C to r.t.
Alkyl Halide, K2CO3
DMF, O° to 70°C
OEt
NH2
OEt
OEt
NaH, DMF, 20°C
S
O
SO2Me
SO2Me
N
R
N
R
N
H
O
2
3a-f
4a-f
1
Synthesis of benzothiazinone derivatives

1414
Y.M. Volovenko, T.A. Volovnenko and K.S. Popov
Vol 44
dioxane to obtain the corresponding methoxy-aldehyde
13e in quantitative yield (Scheme IV).
Scheme II
O
Cl
O
Treatment of the protected compound 8b with
nucleophiles (potassium thiophenolate, sodium ethoxide)
forced the deprotection and the mixture of corresponding
thioacetals and acetals with the aldehyde and starting
dioxolane was isolated.
POCl3, DMF, 0° to 90°C
S
O
S O
O
N
R
N
R
O
4a-b, d-e
5a-b, d-e
The chlorine atom could also be substituted intra-
molecularly. Refluxing hydrazone 7b in DMF for 3 h
Synthesis of chloroaldehydes by Vilsmeier-Haack reaction
Table 1
Physical Data of N-Alkyl-4-chloro-1H-benzo[c][1,2]thiazine-3-carbaldehyde-2,2-dioxides 5a-b,d-e
Yield,
(%)
R
1H NMR (DMSO/TMS) ꢁ, J
(Hz)
13C NMR (DMSO/TMS) ꢁ, m.p., ˚ C
J (Hz)
Mass (CI)
Analysis(%)
Calcd/Found
S,Cl,C,H,N
5a (91)
CH3
3.501 (s, 3H, CH3), 7.492 (t, J =
7.6 Hz, 1H), 7.58 (d, J = 7.8 Hz,
1H), 7.87 (t, J = 8 Hz, 1H), 8,17
(d, J = 7.8 Hz, 1H) 10.107 (s,
1H, CH)
32.1, 119.1, 120.5, 125.1,
129.6, 129.8, 136.6, 141.3,
149.5, 184.2
109-111
238
(M+H)+
12.43 13.79
12.42 13.79
46.61 3.13
46.58 3.10
5.44
5.50
5b (77)
5d (97)
C2H5
1.33 (t, J = 6.8 Hz, 3H), 4.11 (q,
J = 7.2 Hz, 2H), 7.44 (t, J = 7.8
Hz, 1H), 7.60 (d, J = 7.8 Hz,
1H), 7.807 (t, J = 8.2 Hz, 1H),
8,14 (d, J = 8.2 Hz, 1H) 10.10
(s, 1H, CH)
15.0, 43.2, 119.9, 121.4,
125.3, 129.7, 130.5, 136.4,
140.3, 149.3, 183.9
85-87
252
(M+H)+
11.78 13.07
11.77 13.08
48.62 3.71
48.70 3.80
5.15
5.12
n-C4H9
0.95 (t, J = 7.6 Hz, 3H), 1.32
(m, 2H), 1.65 (m, 2H), 4.06 (q, J
= 7.8 Hz, 2H), 7.45 (t, J = 7.8
Hz, 1H), 7.60 (d, J = 7.6 Hz,
1H), 7.81 (t, J = 8.2 Hz, 1H),
8,15 (d, J = 7.8 Hz, 1H) 10.11
(s, 1H, CH)
13.9, 19.8, 30.8, 46.9,
120.0, 121.4, 125.3, 129.7,
130.3, 136.4, 140.3, 149.2,
183.9
52-53
296
(M+H)+
10.68 11.85
10.70 11.83
52.09 4.71
52.19 4.79
4.67
4.72
5e (87)
C6H5CH2
5.28 (s, 2H), 7.23-7.30 (m, 5H),
7.42 (t, J = 7.8 Hz, 1H), 7.48 (d,
J = 7.6 Hz, 1H), 7,707 (t, J =
7.6 Hz, 1H), 8.12 (d, J = 7.8 Hz,
1H), 10.125 (s, 1H, CH)
50.4, 120.6, 121.8, 125.7,
127.8, 128.6, 129.5, 129.7,
130.8, 136.3, 140.2, 149.4,
183.9
114-116
314
(M+H)+
09.60 10.64
09.60 10.63
57.57 3.62
57.52 3.68
4.20
4.24
afforded 5-ethyl-1-phenyl-1,5-dihydrobenzo[c]pyrazolo
[3,4-e][1,2]thiazine 11b. This compound is the first
representative of the new heterocyclic system (SchemeV).
An attempt to employ oxime 6e for analogous
transformation to obtain the corresponding isoxazole did
not succeed and led to ꢀ-chloronitrile 12e. The nitrile was
also the product of the reaction of 6e with sodium hydride
in dry DMF (Scheme V).
Chloronitriles of the type 12, like chloroaldehydes 5,
include 1,3-electrophilic system and could serve as useful
intermediates for the synthesis of more elaborate
structures. In addition to the methods described above,
compounds 12 are accessible by stirring a suspension of
the oxime 6 in benzene with 5 equivalents of excess
thionyl chloride at room temperature overnight (Scheme
V). The yield of target compounds 12 is quantitative.
malononitrile and the 4-chloro-benzenethiol, which
accordingly lead to oximes 6a-b,d-e, hydrazones 7b,e,
[1,3]-dioxolanes 8b,e, methylene-malononitrile 9b and
the (4-chlorophenylsulfanyl)-methanol 10b respectively.
The aldehyde group is a target for all these nucleophiles
(Scheme III).
Our attempt to substitute the chlorine atom in 5b by the
4-chlorophenylthio group failed. Reaction with sodium
methoxide led to an unidentified mixture and so it was
decided to use the protected compounds 8 in all
transformations, concerning the substitution of the
chlorine atom.
For example, the reaction of 8b with sodium methoxide
in methanol leads to the methoxy-dioxolane 8e, followed
by deprotection of 8e by refluxing with HCl in 1,4-

Nov-Dec 2007
Novel Benzothiazine Derivatives
1415
Scheme III
Cl
4-ClC6H4SH, i-PrOH
OH
Cl
OH
Cl
O
Cl
N
NH2OH*HCl, i-PrOH
2h, reflux
S
3 min, reflux
S
O
S O
O
S
O
N
R
N
R
N
R
O
O
10b
5a-b,d-e
6a-b,d-e
CH2(CN)2, i-PrOH
2h, reflux
PhNHNH2, i-PrOH
2h, reflux
ethane-1,2-diol, TsOH
C6H6, Dean-Stark trap
5h, reflux
H
N
Cl
Cl
O
Cl
N
Ph
CN
O
S
O CN
S
O
S
O
N
R
N
R
N
O
O
O
R
7b,e
9b
8b,e
Nucleophilic reactions of the carbonyl moiety
Scheme V
Scheme IV
H
Ph
N
Cl
O
O
O
N
O
O
N
N
N
Cl
N
N
Ph
O
O
MeONa, MeOH
5 min, r.t.
Et3N, DMF
3h, reflux
S
S
S
O
S
O
N
O
O
O
O
8b
8m
7b
11b
O
O
HCl, dioxane:water (1:1)
10min, r.t.
OH
Cl
N
Cl
S
O
a. Et3N, DMF, 3h, reflux
b. NaH, DMF, 5h, r.t.
N
CN
O
c.
SOCl2, benzene, overnight, r.t.
13e
S
O
S O
O
N
R
N
R
O
Selectivity achieved using protected intermediate
6a-b,e
12a-b,e
There is important distinction between 12 and 5 that has
to be considered when planning synthesis. In
chloroaldehydes, carbonyl is more reactive toward
nucleophiles than C-4 center, but we assumed that in
chloronitriles the substitution of the chlorine atom would
be much faster then the nucleophilic addition to the nitrile
group. This assumption was verified experimentally.
Thus, by refluxing the mixture of 12, dimethylamine and
triethylamine in ethanol dimethylamino-derivatives 14
were obtained (Scheme VI).
Benzothiazine derivatives transformations
Scheme VI
Cl
N
CN
CN
O
Me2NH*HCl, Et3N
EtOH, reflux, 5h
S
O
S
N
R
N
O
O
R
Consequently, every two-stage heterocyclisation
process starts with nucleophilic attack at the C-4 position
of the ꢀ-chloronitrile followed by the addition to the
nitrile group resulting in the ring closure. The reaction of
12 with methyl thioglycolate proceeds by reflux in
isopropanol with potassium carbonate in two stages
(Scheme VII). The nucleophilic substitution by the
thioglycolate anion led to sulfanylacetic acid methyl ester
15 which is not isolated pure but is rapidly converted to
the thiophene-amino carboxylic acid ester 16. The
progress of the heterocyclisation is easy to control by
means of 1H-NMR, measured from the mixture.
12a-b
14a-b
Displacement of chlorine by dimetylamine
Aminopyrazoles 17 are accessible by refluxing 12 with
the corresponding hydrazine in isopropanol with
potassium carbonate With N-substituted hydrazine only
one isomer is formed in both cases. The two-step process
starting from fast chlorine substitution (Scheme VIII) is
analogous to the thioglycolic ester cyclisation.

1416
Y.M. Volovenko, T.A. Volovnenko and K.S. Popov
Vol 44
Scheme VII
CO2Me
Cl
S
CO2Me
CN
S
CN
O
NH2
O
Methyl thioglycolate, K2CO3
i-PrOH, 25° to 80°C, 5h
S
S
O
S
N
N
N
O
O
O
Me
Me
Me
16
12a
15
Synthesis of thieno-annelated benzothiazine
Scheme VIII
EXPERIMENTAL
The NMR spectra were measured on
R
a
Varian 400
N
Cl
N
spectrometer at 25°C using DMSO-d6. All chemical shifts are
reported in ppm relative to TMS. Starting materials used were
obtained from Makrochim and used without further purification.
Dry solvents were prepared according to the standard methods.
CN
O
NH2
RNHNH2, K2CO3
i-PrOH, reflux, 5h
S
S O
O
N
N
O
Me
Me
Ethyl
2-alkylmethylsulfonylamido-benzoates
(3a-f);
General Procedure. To a magnetically stirred solution of ethyl
2-methylsulfonylamidobenzoate (19.3 g, 78 mmol) in dry DMF
(35 mL) at 0 °C was added potassium carbonate (22 g, 0.16
mol). The reaction mixture was stirred for 15 min at 0 °C, then
the alkyl halide (100 mmol) was added dropwise. The mixture
12a
17a (R=H)
17b (R=Ph)
-C H -NO
)
2
17c (R=
6
4
Synthesis of pyrazolo-annelated benzothiazine
Table 2
Physical Data of N-Alkyl-1H-benzo[c][1,2]thiazin-4-one-2,2-dioxides 4a-f
Yield, (%)
R
m.p., ˚ C
1H NMR (DMSO/TMS) ꢁ, J (Hz)
IR (KBr)
4a (67)
CH3
107-108
3.37 (s, 3H, CH3), 4.96 (s, 2H, CH2), 7.30 (t, J = 7.6 Hz, 1H), 7.42 2973, 2920, 1687, 1599,
(d, J = 8.4 Hz, 1H), 7.78 (t, J = 8 Hz, 1H), 8.00 (d, J = 8 Hz, 1H)
1.28 (t, J = 6.8 Hz, 3H), 4.02 (q, J = 7.2 Hz, 2H), 4.91 (s, 2H,
CH2), 7.28 (t, J = 7.2 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.76 (t, J
= 7.2 Hz, 1H), 8.00 (d, J = 8 Hz, 1H)
1457,1332, 1318, 1146 cm-1
2987, 2925, 1680, 1579,
1453,1342, 1321, 1151 cm-1
4b (66)
4c (98)
4d (70)
4e (90)
4f (94)
C2H5
86-88
n-C3H7
84-86
49-51
79-81
72-73
0.99 (t, J = 6.7 Hz, 3H), 1.75 (m, 2H), 3.88 (t, J = 7 Hz, 2H), 4.70
(s, 2H, CH2), 7.23 (t, J = 7.2 Hz, 1H), 7.36 (d, J = 8.2 Hz, 1H),
7.70 (t, J = 6.8 Hz, 1H), 8.01 (d, J = 8 Hz, 1H)
2987, 2925, 1682, 1589,
1467,1340, 1289, 1157 cm-1
n-C4H9
0.92 (q, J = 7.2 Hz, 3H), 1.31 (m, 2H), 1.65 (m, 2H), 4.06 (t, J = 8 2961, 2873, 1684, 1598,
Hz, 2H), 4.70 (s, 2H, CH2), 7.46 (t, J = 7.6 Hz, 1H), 7.70 (d, J =
8.4 Hz, 1H), 7.82 (t, J = 8 Hz, 1H), 8.02 (d, J = 7.6 Hz, 1H)
4.69 (s, 2H), 5.35 (s, 2H, CH2), 7.29-7.37 (m, 5H, phenyl), 7.51 (t,
J = 6.8 Hz, 1H), 7.62 (d, J = 8 Hz, 1H), 7.71 (t, J = 7.6 Hz, 1H),
8.02 (d, J = 6.8 Hz, 1H)
1477,1339, 1297, 1154 cm-1
C6H5CH2
2-ClC6H4CH2
2926, 1687, 1598, 1349,
1226, 1162 cm-1
4.72 (s, 2H), 5.41 (s, 2H), 7.24-7.32 (m, 4H), 7.54 (t, J = 6.8 Hz,
1H), 7.65 (d, J = 6.8 Hz, 1H), 7.72 (t, J = 6.8 Hz, 1H), 8.04 (d, J
= 6.8 Hz, 1H)
3435, 2985, 1689, 1476,
1347, 1160 cm-1
was slowly heated to 70 °C. After 8 hours, the inorganics were
filtered off, the solution was concentrated in vacuo and the crude
product was washed with water and filtered (oily products were
extracted in chloroform 3x150mL, washed with water, dried and
the solvent evaporated in vacuo). The pure product was obtained
by crystallisation from i-PrOH (61-88%).
Product 3a (73%): m.p.: 56-58 ˚C; ꢀH NMR (400 MHz,
DMSO): ꢁ = 1.29 (t, J = 7.6 Hz, 3H), 2.98 (s, 3H), 3.22 (s, 3H),
4.25 (q, J = 7.8 Hz, 2H), 7.47 (t, J = 8 Hz, 1H), 7.57 (d, J = 7.8
Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.73 (d, J = 8.2 Hz, 1H); MS
(CI): 258(M+H)+.
Structures of all above-mentioned compounds were
1
established on the basis of their H NMR, 13C NMR, IR
spectral data, mass spectrometry data and elemental
microanalyses.
In conclusion, a synthesis of N-alkyl-4-chloro-1H-
benzo[c][1,2]thiazine-3-carbaldehyde-2,2-dioxides 5a-b,
d-e from N-alkyl-1H-benzo[c][1,2]thiazin-4-one-2,2-
dioxides is disclosed. The investigation of the reactivity of
the new ꢀ-chloroaldehydes was carried out resulting in the
preparation of a number of previously unknown benzo[c]-
[1,2]thiazine derivatives.
Product 3b (82%): m.p.: 61-63 ˚C; ꢀH NMR (400 MHz,
DMSO): ꢁ = 1.06 (t, J = 7.8 Hz, 3H), 1.29 (t, J = 8.2 Hz, 3H),

Nov-Dec 2007
Novel Benzothiazine Derivatives
1417
2.95 (s, 3H), 3.67 (q, J = 8 Hz, 2H), 4.25 (q, J = 7.8 Hz, 2H),
7.48 (t, J = 7.6 Hz, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.64 (t, J = 7.6
Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H); MS (CI): 273(M+H)+.
Product 3c (75%): m.p.: 35-37 ˚C; ꢀH NMR (400 MHz,
DMSO): ꢀ = 0.82 (t, J = 7.6 Hz, 3H), 1.29 (t, J = 7.4 Hz, 3H),
1.46 (m, 2H), 2.95 (s, 3H), 3.56 (br.s, 2H), 4.24 (q, J = 7.8 Hz,
2H), 7.47 (t, J = 7.8 Hz, 1H), 7.55 (s, 1H), 7.63 (t, J = 8.2 Hz,
1H), 7.77 (d, J = 8 Hz, 1H); MS (CI): 287(M+H)+.
Product 3d (oil, 61%): ꢀH NMR (400 MHz, DMSO): ꢀ =
0.92 (t, J = 8.2 Hz, 3H), 1.29 (t, J = 8 Hz, 3H), 1.31 (m, 2H),
1.65 (m, 2H), 2.90 (s, 3H), 4.06 (br.s, 2H), 4.23 (q, J = 7.8 Hz,
2H,), 7.45 (t, J = 7.6 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.79 (t, J
= 7.6 Hz, 1H), 7.89 (d, J = 8 Hz, 1H); MS (CI): 300(M+H)+.
Product 3e (oil, 88%): ꢀH NMR (400 MHz, DMSO): ꢀ = 2.92
s, 3H), 5.25 (br.s, 2H), 7.28-7.35 (m, 5H), 7.45 (t, J = 7.8 Hz,
1H), 7.52 (d, J = 7.6 Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H), 7.81 (s,
1H); MS (CI): 334(M+H)+.
11.16; Cl, 12.38; C, 46.08; H, 3.87; N, 9.77; found S, 11.17; Cl,
12.45; C, 46.12; H, 3.91; N, 9.80.
Product 6d (67%): m.p.: 142-143 ˚C; ꢀH NMR (400 MHz,
DMSO): ꢀ = 0.90 (t, J = 6.8 Hz, 3H), 1.28 (sex, J = 6.8 Hz, 2H),
1.61 (q, J = 7 Hz, 2H), 4.01 (t, J = 7.6 Hz, 2H), 7.36 (t, J = 7.8
Hz, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.97
(d, J = 8 Hz, 1H) 8.19 (s, 1H), 12.36 (s, 1H); 13C NMR (100
MHz, DMSO): ꢀ = 13.9, 19.7, 30.6, 47.8, 120.4, 122.5, 125.2,
128.4, 129.7, 133.7, 137.0, 138.5, 141.2; Anal.calcd. S, 10.16;
Cl, 11.27; C, 49.60; H, 4.80; N, 8.90; found S, 10.17; Cl, 11.3;
C, 49.63; H, 4.85; N, 8.92.
Product 6e (62%): m.p.: 210-212 ˚C; ꢀH NMR (400 MHz,
DMSO): ꢀ = 5.22 (s, 2H), 7.20-7.32 (m, 5H), 7.35 (t, J = 7.8 Hz,
1H), 7.41 (d, J = 7.8 Hz, 1H), 7.55 (t, J = 7.6 Hz, 1H), 7.94 (d, J
= 7.8 Hz, 1H), 8.18 (s, 1H), 12.43 (s, 1H); 13C NMR (100 MHz,
DMSO): ꢀ = 50.5, 119.9, 122.1, 124.9, 125.1, 126.3, 126.9,
127.5, 128.0, 129.5, 133.3, 136.9, 138.2, 140.9; Anal. calcd. S,
9.17; Cl, 10.17; C, 49.10; H, 3.96; N, 9.16; found S, 9.17; Cl,
10.18; C, 49.14; H, 4.02; N, 9.19.
4-Chloro-1-alkyl-(1H)-2,1-benzothiazin-3-carbaldehyde-2,2-
dioxide N-phenylhydrazones (7b,e); General Procedure. To a
solution of ꢁ-chloroaldehyde (5b,e) (250 mg, 1 mmol) in ꢀ-PrOH
(2 mL) was added phenylhydrazine (120 mg, 1.2 mmol). The
mixture was heated to reflux for 5 hours. After cooling to rt. the
solid product was filtered and washed with ꢀ-PrOH to afford
pure target compound (68-75%).
Product 7b (75%): ꢀH NMR (400 MHz, DMSO): ꢀ = 1.31 (t,
J = 6.8 Hz, 3H), 4.08 (q, J = 6.8 Hz, 2H), 6.84 (t, J = 7 Hz, 1H),
7.13 (d, J = 7.8 Hz, 2H), 7.235 (t, J = 7.8 Hz ,2H), 7.35 (t, J =
7.6 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.56 (t, J = 8 Hz, 1H),
7.94 (d, J = 7.8 Hz, 1H), 7.99 (s, 1H), 11.02 (s, 1H); 13C NMR
(100 MHz, DMSO): ꢀ = 14.7, 44.2, 113.6, 120.3, 121.3, 123.2,
125.2, 127.5, 127.9, 130.0, 131.1, 132.3, 133.0, 137.9, 144.6;
Anal. calcd. S, 8.84; Cl, 9.81; C, 56.43; H, 4.46; N, 11.61; found
S, 8.8; Cl, 9.82; C, 56.47; H, 4.42; N, 11.57.
Product 7e (68%): ꢀH NMR (400 MHz, DMSO): ꢀ = 5.21 (s,
2H), 6.82 (t, J = 6.8 Hz, 2H), 7.12- 7.35 (m, 11H), 7.44 (t, J =
7.8 Hz, 1H), 7.89 (d, J = 7.6 Hz, 1H) 8.0 (s, 1H), 11.0 (s, 1H);
13C NMR (100 MHz, DMSO): ꢀ = 51.6, 113.6, 120.6, 121.3,
123.3, 125.3, 127.5, 127.7, 127.9, 128.4, 128.5, 129.0, 129.3,
130.0, 131.1, 132.1, 133.1, 136.7, 137.8, 144.6; Anal. calcd. S,
7.55; Cl, 8.37; C, 62.33; H, 4.28; N, 9.91; found S, 7.55; Cl, 8.4;
C, 62.31; H, 4.24; N, 9.95.
4-Chloro-3-(1,3-dioxolan-2-yl)-1-alkyl-(1H)-2,1-benzothia-
zin-2,2-dioxides; General Procedure (8b,e). To a mixture of ꢁ-
chloroaldehyde (5b,e) (500 mg, 2 mmol) and ethane-1,2-diol (3
mmol) in dry benzene (15 mL) the catalytic amount of 4-
tolylsulfonic acid (5 mol%) was added. The reaction flask was
equipped with a Dean-Stark trap and the mixture was refluxed
for 5 hours. After cooling to r.t. the organic layer was separated,
washed extensively with water and evaporated in vacuo to afford
yellow solid, which was puified by crystallysation from i-PrOH.
Product 8b (87%): m.p.: 121-123 ˚C; ꢀH NMR (400 MHz,
DMSO): ꢀ = 1.24 (t, J = 7 Hz, 3H), 3.97-4.05 (m, 4H), 4.20 (q,
J = 7.2 Hz, 2H), 6.29 (s, 1H), 7.37 (t, J = 7.8 Hz, 1H), 7.52 (d, J
= 7.6 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.98 (d, J = 7.8 Hz, 1H);
13C NMR (100 MHz, DMSO): ꢀ = 14.3, 44.2, 66.4, 100.9, 112.2,
120.5, 122.6, 125.2, 128.5, 132.7, 133.8, 138.9, 139.4; Anal.
calcd. S, 10.13; Cl, 11.24; C, 49.45; H, 4.47; N, 4.44; found S,
10.12; Cl, 11.04; C, 49.49; H, 4.43; N, 4.45.
Product 3f (oil, 78%): ꢀH NMR (400 MHz, DMSO): ꢀ = 2.96
(s, 3H), 5.34 (br.s, 2H), 7.23-7.30 (m, 4H), 7.44 (t, J = 7.6 Hz,
1H), 7.55 (d, J = 7.8 Hz, 1H), 7.63 (t, J = 8 Hz, 1H), 7.83 (d, J =
7.6 Hz, 1H); MS (CI): 368(M+H)+.
N-Alkyl-3,4-dihydro-(1H)-2,1-benzothiazin-4-one-2,2-
dioxides (4a-f), Table 2; General Procedure. To a
magnetically stirred suspension of sodium hydride (120 mmol)
in dry DMF (15 mL) at r.t., the solution of alkylated product
(3a-f) (60 mmol) in dry DMF was added dropwise (25 mL).
After hydrogen evolution was over, the mixture was stirred for 4
hours, DMF was evaporated, and dilute hydrochloric acid (250
mL) was added to the residue. The crude product was collected
by filtered and washed with water. Recrystallisation from i-
PrOH afforded pure target products (67-98%).
4-Chloro-1-alkyl-(1H)-2,1-benzothiazin-3-carbaldehyde-
2,2-dioxides (5a-b,d-e), Table 1; General Procedure. To
magnetically stirred dry DMF (14 mL) at 0 ˚C was added
phosphorus oxychloride (8.3 mL, 40 mmol). After 30 minutes at
0 ˚C the solution of benzothiazine-4-one (4a-b,d-e, 10 mmol) in
dry DMF was added dropwise. The mixture obtained was stirred
for 10 hours, then the temperature was gradually raised to 75 ˚C.
The solution was concentrated in vacuo. To the resulting brown
oil ice was added (250 mL) and the mixture was filtered to yield
pure product (77-97%).
4-Chloro-1-alkyl-(1H)-2,1-benzothiazin-3-carbaldehyde-
2,2-dioxide oximes (6a-b,d-e); General Procedure. To a
solution of ꢁ-chloroaldehyde (5a-b,d-e) (250 mg, 1 mmol) in ꢀ-
PrOH (2 mL) was added hydroxylamine hydrochloride (90 mg,
3 mmol). The mixture was heated to reflux for 3 hours. After
cooling to r.t the solid product was filtered and washed with ꢀ-
PrOH to afford pure target compound (62-89%).
Product 6a (80%): m.p.: 203-205 ˚C; ꢀH NMR (400 MHz,
DMSO): ꢀ = 3.50 (s, 3H), 7.36 (t, J =7.6 Hz, 1H), 7.46 (d, J =
7.8 Hz, 1H), 7.66 (t, J = 8 Hz, 1H), 7.98 (d, J = 7.8 Hz, 1H) 8.19
(s, 1H), 12.37 (s, 1H);
13C NMR (100 MHz, DMSO): ꢀ = 33.0, 119.2, 121.3, 124.9,
128.3, 128.8, 133.9, 137.5, 139.5, 141.3; Anal.calcd. S, 11.73;
Cl, 13.02; C, 44.04; H, 3.33; N, 10.27; found S, 11.75; Cl,
13.02; C, 44.09; H, 3.38; N, 10.32.
Product 6b (89%): m.p.: 179-181 ˚C; ꢀH NMR (400 MHz,
DMSO): ꢀ = 1.30 (t, J = 6.8 Hz, 3H), 4.08 (q, J = 7 Hz, 2H),
7.37 (t, J = 6.8 Hz, 2H), 7.54 (d, J = 7.6 Hz, 1H), 7.66 (t, J = 7.8
Hz, 1H), 7.98 (d, J = 8.2 Hz, 1H) 8.19 (s, 1H), 12.40 (s, 1H);
13C NMR (100 MHz, DMSO): ꢀ = 14.7, 44.2, 120.3, 122.4,
125.2, 128.4, 129.9, 133.7, 137.2, 138.5, 141.3; Anal. calcd. S,
Product 8e (70%): m.p.: 149-151 ˚C; ꢀH NMR (400 MHz,
DMSO): ꢀ = 4.01 (m, 2H), 4.22 (m, 2H), 5.21 (s, 2H), 6.33 (s,

1418
Y.M. Volovenko, T.A. Volovnenko and K.S. Popov
Vol 44
1H), 7.22-7.33 (m, 6H), 7.41 (d, J = 7.8 Hz, 1H) 7.53 (t, J = 7.8
Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H); 13C NMR (100 MHz, DMSO):
ꢀ = 50.7, 66.1, 100.6, 111.9, 120.2, 122.3, 125.1, 126.8, 127.5,
127.6, 128.1, 128.2, 132.4, 133.4, 138.5, 139.1; Anal.calcd. S,
8.47; Cl, 9.39; C, 57.22; H, 4.27; N, 3.71; found S, 8.51; Cl,
9.42; C, 57.12; H, 4.31; N, 3.77.
2-(4-Chloro-1-ethyl-(1H)-2,1-benzothiazin-2,2-dioxide-3-yl-
methylene)malononotrile (9b). To a solution of ꢁ-chloro-
aldehyde (5b) (250 mg, 1 mmol) in i-PrOH (2 mL) was added
malononitrile (1 mmol). The mixture was heated to reflux for 2
hours. After cooling to r.t the solid product was filtered and
washed with i-PrOH to afford pure target compound (73%).
M.p.: 109-111 ˚C; ꢀH NMR (400 MHz, DMSO): ꢀ = 1.30 (t, J =
8 Hz, 3H), 4.12 (q, J = 8 Hz, 2H), 7.49 (t, J = 7.8 Hz, 1H), 7.68
(d, J = 7.6 Hz, 1H), 7.81 (t, J = 7.8 Hz, 1H), 8.10 (d, J = 7.8 Hz,
1H), 8.92 (s, 1H); 13C NMR (100 MHz, DMSO): ꢀ = 14.3, 44.8,
91.2, 111.8, 113.3, 120.7, 122.3, 125.8, 128.5, 129.7, 135.6,
139.3, 144.6, 149.2; Anal.calcd. S, 10; Cl, 11.1; C, 52.59; H,
3.15; N, 13.14; found S, 9.88; Cl, 10.9; C, 52.63; H, 3.20; N,
13.19.
4-Chloro-1-ethyl-(1H)-2,1-benzothiazin-2,2-dioxide-3-yl-
(4-chlorophenylsulfanyl)methanol (10b). To a solution of ꢁ-
chloroaldehyde (5b) (250 mg, 1 mmol) in i-PrOH (2 mL) was
added 4-chlorothiophenol (1 mmol). The mixture was heated to
reflux for 3 minutes. After cooling to r.t the solid product was
filtered and washed with i-PrOH to afford pure target compound
(96%). M.p.: 184-186 ˚C; ꢀH NMR (400 MHz, DMSO): ꢀ = 1.31
(t, J = 8 Hz, 3H), 4.01 (q, J = 7.8 Hz, 2H), 6.13 (s, 1H), 7.29 (t, J
= 7.8 Hz, 1H) 7.48 (d, J = 7.6 Hz, 1H), 7.53-7.62 (m, 6H), 7.93
(d, J = 7.8 Hz, 1H); 13C NMR (100 MHz, DMSO): ꢀ = 14.7,
41.5, 119.5, 119.6, 121.2, 124.1, 127.2, 128.0, 131.2, 133.0,
136.1, 136.9, 138.9, 146.5; Anal.calcd. S, 15.37; Cl, 17.05; C,
49.04; H, 3.63; N, 3.36; found S, 15.24; Cl, 17.1; C, 49.14; H,
3.58; N, 3.41.
N-Phenyl-5-ethyl-1,5-dihydrobenzo[C]pyrazolo[3,4-e][1,2]-
thiazin-2,2-dioxide (11b). 4-Chloro-1-ethyl-(1H)-2,1-benzo-
thiazine-3-carbaldehyde-2,2-dioxide N-phenylhydrazone (7b)
(300 mg, 0.9 mmol) was dissolved in dry DMF (1.5 mL), the
catalytic amount of triethylamine was added and the mixture
obtained was heated to reflux for 2 hours. The solution was
concentrated in vacuo, solid product was washed with ethanol
and filtered, which gave the title pure product (74%). M.p.: 151-
153 ˚C; ꢀH NMR (400 MHz, DMSO): ꢀ = 1.25 (t, J = 6.8 Hz,
3H), 4.01 (q, J = 7 Hz, 2H), 6.99-7.05 (m, 2H), 7.46-7.63 (m,
7H) 8.17 (s, 1H); 13C NMR (100 MHz, DMSO): ꢀ = 14.1, 43.6,
117.0, 119.7, 122.7, 124.9, 125.2, 127.4, 130.7, 130.9, 131.8,
133.6, 138.1, 138.8, 139.7; Anal.calcd. S, 9.83; N, 12.91; C,
62.75; H, 4.65; N, 12.91; found S, 9.84; N, 12.94; C, 62.81; H,
4.70; N, 12.97.
1-Benzyl-4-chloro-1H-2,1-benzothiazin-3-carbonitrile 2,2-
dioxide (12e); Alternative Method. A solution of 4-chloro-1-
benzyl-(1H)-2,1-benzothiazine-3-carbaldehyde-2,2-dioxide ox-
ime (6e) (300 mg, 0.9 mmol) in dry DMF (0.5 mL) was added
dropwise to a suspension of sodium hydride in dry DMF (1 mL).
The resulting mixture was stirred for 2 hours. The solution was
concentrated in vacuo, solid product filtered, which gave the title
pure product (97%).
1-Alkyl-4-chloro-1H-2,1-benzothiazin-3-carbonitrile 2,2-
dioxides (12a,b); General Procedure. Thionyl chloride (3.6
mL, 0.05 mol) was added dropwise to a suspension of 4-chloro-
1-alkyl-(1H)-2,1-benzothiazine-3-carbaldehyde-2,2-dioxide ox-
ime (6a,b) (2.5 g, 0.01 mol) in dry benzene (10 mL). The
resulting mixture was stirred at room temperature overnight. The
excess thionyl chloride and benzene were distilled off in vacuo,
solid product washed with ethanol, collected by filtration and
dried which gave the title pure compound (quantitative).
Product 12a (99%): m.p.: 153-154 ˚C; ꢀH NMR (400 MHz,
DMSO): ꢀ = 3.61 (s, 3H), 7.50 (t, J = 7.8 Hz, 1H), 7.64 (d, J = 8
Hz, 1H), 7.86 (t, J = 8.2 Hz, 1H), 8.06 (d, J = 7.8 Hz, 1H); MS
(CI): 255(M+H)+; Anal. calcd. S, 12.59; N, 11.00; C, 47.16; H,
2.77; N, 11.00; found S, 12.88; N, 10.91; C, 47.19; H, 2.82; N,
11.15.
Product 12b (99%): m.p.: 130-132 ˚C; ꢀH NMR (400 MHz,
DMSO): ꢀ = 1.25 (t, J = 7.4 Hz, 3H), 3.92 (q, J = 7.4 Hz, 2H),
7.47 (t, J = 7.8 Hz, 1H), 7.61 (d, J = 8 Hz, 1H), 7.82 (t, J = 8.2
Hz, 1H), 8.02 (d, J = 8.2 Hz, 1H); MS (CI): 269(M+H)+; Anal.
calcd. S, 11.93; N, 10.42; C, 49.17; H, 3.38; N, 10.42; found S,
11.81; N, 10.13; C, 49.21; H, 3.44; N, 10.49.
1-Ethyl-4-methoxy-1H-2,1-benzothiazin-3-carbaldehyde 2,2-
dioxide (13e). 4-Methoxy-3-(1,3-dioxolan-2-yl)-1-ethyl-(1H)-
2,1-benzothiazin-2,2-dioxide (8m) (0.5 g, 0.16 mmol) was
dissolved in 1,4-dioxane:water (1:1). Hydrochloric acid (3mL,
conc.) was added to the solution and the mixture was stirred for
10min at room temperature. Solution was concentrated, solid
product filtered and dried to give the pure title compound (97%).
M.p.: 134-135 ˚C; ꢀH NMR (400 MHz, DMSO): ꢀ = 1.30 (t, J =
6.8 Hz, 3H), 3.87 (s, 3H), 4.08 (q, J = 7.2 Hz, 2H), 7.46 (t, J =
7.8 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.84 (t, J = 8.2 Hz, 1H),
8,02 (d, J = 8.2 Hz, 1H), 9.75 (s, 1H); MS (CI): 268 (M+H)+;
Anal.calcd. S, 12.00; N, 5.24; C, 53.92; H, 4.90; N, 5.24; found
S, 12.17; N, 5.65; C, 53.98; H, 4.93; N, 5.29.
1-Alkyl-4-(N,N-dimethylamino)-1H-2,1-benzothiazin-3-
carbonitrile 2,2-dioxides (14a,b); General Procedure. A
solution of 4-chloro-1-alkyl-(1H)-2,1-benzothiazine-3-carbo-
nitrile-2,2-dioxide (12a,b) (250 mg, 0.1 mmol), dimethylamine
hydrochloride (100 mg, 0.12 mmol) and triethylamine (3 mL) in
ethanol (10 mL) was refluxed for 5 hours. Solid product was
collected by filtration, washed with ethanol and dried, which
gave the title pure compound.
Product 14a (89%): m.p.: 161-162 ˚C; ꢀH NMR (400 MHz,
DMSO): ꢀ = 3.26 (s, 6H), 3.35 (s, 3H), 7.33 (t, J = 7.8 Hz, 1H),
7.46 (d, J = 8 Hz, 1H), 7.68 (t, J = 7.8 Hz, 1H), 7.79 (d, J = 8
Hz, 1H); MS (CI): 264(M+H)+; Anal. calcd. S, 12.18; N, 15.96;
C, 54.74; H, 4.98; N, 15.96; found S, 11.89; N, 15.94; C, 54.80;
H, 5.12; N, 16.08.
Product 14b (94%): m.p.: 142 ˚C; ꢀH NMR (400 MHz,
DMSO): ꢀ = 1.27 (t, J = 7.4 Hz, 3H), 3.24 (s, 6H), 3.95(q, J =
7.4 Hz, 2H), 7.36 (t, J = 7.8 Hz, 1H), 7.54 (d, J = 7.8 Hz, 1H),
7.71 (t, J = 8.2 Hz, 1H), 7.81 (d, J = 8 Hz, 1H); MS (CI):
278(M+H)+; Anal. calcd. S, 11.56; N, 15.15; C, 56.30; H, 5.45;
N, 15.15; found S,11.50; N, 15.10; C, 56.36; H, 5.49; N, 15.21.
1-Benzyl-4-chloro-1H-2,1-benzothiazine-3-carbonitrile 2,2-
dioxide (12e). 4-Chloro-1-benzyl-(1H)-2,1-benzothiazine-3-
carbaldehyde-2,2-dioxide oxime (6e) (300 mg, 0.9 mmol) was
dissolved in dry DMF (1 mL), catalytic amount of triethylamine
was added and the mixture obtained was heated to reflux for 12
hours. The solution was concentrated in vacuo, solid product
filtered, which gave the title pure product (65%). ꢀH NMR (400
MHz, DMSO): ꢀ = 5.01 (s, 2H), 7.07 (d, 1H), 7.16 (t, 1H), 7.2-
7.34 (m, 5H), 7.38 (t, 1H), 7.91 (d, 1H); 13C NMR (100 MHz,
DMSO): ꢀ = 50.5, 111.9, 119.3, 120.2, 122.3, 124.9, 126.3,
127.1, 127.6, 128.3, 129.8, 129.0, 132.4, 133.4, 138.54, 139.1;
Anal.calcd. S, 9.67; Cl, 10.73; C, 58.10; H, 3.35; N, 8.47; found
S, 9.65; Cl. 10.74; C, 58.16; H, 3.39; N, 8.52.

Nov-Dec 2007
Novel Benzothiazine Derivatives
1419
1H), 7.27 (d, J = 8.2 Hz, 1H), 7.45-7.63 (m, 6H, Ph+H), 7.94 (d,
J = 8.2 Hz, 1H); MS (CI): 327(M+H)+; Anal. calcd. S, 9.82; C,
58.88; H, 4.32; N, 17.17; found S, 9.88; C, 58.81; H, 4.26; N,
17.54.
Product 17c (67%): m.p.: 240-241 ˚C; ꢀH NMR (400 MHz,
DMSO): ꢀ = 3.28 (s, 3H), 6.72 (s, 2H, NH2), 7.28 (t, J = 7.8 Hz,
1H), 7.34 (d, J = 8 Hz, 1H), 7.49 (t, J = 8.2 Hz, 1H), 7.93-7.95
(m, 3H, Ph+H), 8.37 (m, 2H, Ph); MS (CI): 371(M+H)+; Anal.
calcd. S, 8.63; C, 51.75; H, 3.53; N, 18.86; found S, 8.43; C,
51.70; H, 3.58; N, 18.98.
Methyl 3-amino-5-methyl-5H-thieno[3,2-c][2,1]benzothiaz-
ine-2-carboxylate 2,2-dioxide (16). A mixture of 4-chloro-1-
methyl-(1H)-2,1-benzothiazine-3-carbonitrile-2,2-dioxide (12a)
(250 mg, 0.1 mmol), methyl thioglycolate (0.1 mL, 0.12 mmol)
and potassium carbonate (200 mg, 0.15 mmol) in isopropanol
(10 mL) was stirred at gradual temperature raise of 25 ˚C to 80
˚C for 5 hours. Solid product was filtered, washed with water,
dried and recrystallized from acetic acid to give the title pure
compound (86%). M.p.: 189-191 ˚C; ꢀH NMR (400 MHz,
DMSO): ꢀ = 3.46 (s, 3H), 3.84 (s, 3H), 6.46 (s, 2H, NH2), 7.33
(t, J = 7.8 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.61 (t, J = 8 Hz,
1H), 7.73 (d, J = 8.2 Hz, 1H); MS (CI): 326(M+H)+; IR (KBr):
1150, 1300cm-1 (SO2), 1692cm-1 (C=O), 3360, 3480cm-1
(NH2); Anal. calcd. S, 19.77; N, 8.64; C, 48.14; H, 3.73; N,
8.64; found S, 19.87; N, 8.72; C, 48.20; H, 3.81; N, 8.68.
REFERENCES
[1] Catsoulacos P., Camoutsis C., J. Heterocyclic Chem., 1979,
16, 1503.
2-R-5-methyl-2,5-dihydropyrazolo[4,3-c][2,1]benzothiazin
-3-amine 2,2-dioxides (17a,b,c); General Procedure.
[2] (a) Love B., Kormendy M.F., Snader K.M., J. Org. Chem.,
1966, 31, 3531; (b) Rossi S., Pagani G., Ann. Chim. (Rome), 1966, 56,
741; C.A., 1966, 65, 10502h..
A
mixture of 4-chloro-1-methyl-(1H)-2,1-benzothiazine-3-carbo-
nitrile-2,2-dioxide (12a) (250 mg, 0.1 mmol), corresponding
hydrazine (0.12 mmol) and potassium carbonate (200 mg, 0.15
mmol) in isopropanol (10 mL) was refluxed for 10 hours. Solid
product was collected by filtration, washed with water and
recrystallized from isopropanol to give the title pure compound.
Product 17a (75%): m.p.: 201-203 ˚C; ꢀH NMR (400 MHz,
DMSO): ꢀ = 3.27 (s, 3H), 5.75-5.90 (br.s, 3H, NH2+NH), 7.20-
7.27 (m, 2H, arom), 7.43 (t, J = 7.8 Hz, 1H), 7.90 (d, J = 8.2 Hz,
1H); MS (CI): 251(M+H)+; Anal. calcd. S, 12.81; C, 47.99; H,
4.03; N, 22.39; found S, 12.92; C, 47.92; H, 4.00; N, 22.91.
Product 17b (72%): m.p.: 166-167 ˚C; ꢀH NMR (400 MHz,
DMSO): ꢀ = 3.26 (s, 3H), 6.17 (s, 2H, NH2), 7.23 (t, J = 7.8 Hz,
[3] Coppo F., Fawzi M., J. Heterocyclic Chem., 1998, 35, 499.
[4] Coppo F., Fawzi M., J. Heterocyclic Chem., 1998, 35, 983.
[5] Lombardino J., J. Heterocyclic Chem., 1972, 9, 315.
[6] Dalmaris J., Hanson J.R., J. Chem. Res., Synop., 2003, 3,
150-152.
[7] Migianu E., Kirsh G., Synthesis, 2002, 8, 1096-1100.
[8] Venkati M., Krupadanam G., Synth. Commun., 2001, 17,
2589-2598.
[9] Chen C.H., Preynolds G. A., J. Org. Chem., 1979, 44, 18,
3144-3147.
[10] Ricci A., Balucani D., Fravolini A., GAZZ. CHIM. ITAL.,
1977, 107, 1-2, 19-26.